title: An epistatic interaction between the PAX8 and STK17B genes in papillary thyroid cancer susceptibility.
abstract: Papillary Thyroid Cancer (PTC) is a heterogeneous and complex disease; susceptibility to PTC is influenced by the joint effects of multiple common, low-penetrance genes, although relatively few have been identified to date. Here we applied a rigorous combined approach to assess both the individual and epistatic contributions of genetic factors to PTC susceptibility, based on one of the largest series of thyroid cancer cases described to date. In addition to identifying the involvement of TSHR variation in classic PTC, our pioneer study of epistasis revealed a significant interaction between variants in STK17B and PAX8. The interaction was detected by MD-MBR (p = 0.00010) and confirmed by other methods, and then replicated in a second independent series of patients (MD-MBR p = 0.017). Furthermore, we demonstrated an inverse correlation between expression of PAX8 and STK17B in a set of cell lines derived from human thyroid carcinomas. Overall, our work sheds additional light on the genetic basis of thyroid cancer susceptibility, and suggests a new direction for the exploration of the inherited genetic contribution to disease using association studies.
authors.affiliation: Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre, Madrid, Spain.
authors.forename: Iñigo
authors.initials: I
authors.lastname: Landa
authors.forename: Cesar
authors.initials: C
authors.lastname: Boullosa
authors.forename: Lucía
authors.initials: L
authors.lastname: Inglada-Pérez
authors.forename: Ana
authors.initials: A
authors.lastname: Sastre-Perona
authors.forename: Susana
authors.initials: S
authors.lastname: Pastor
authors.forename: Antonia
authors.initials: A
authors.lastname: Velázquez
authors.forename: Veronika
authors.initials: V
authors.lastname: Mancikova
authors.forename: Sergio
authors.initials: S
authors.lastname: Ruiz-Llorente
authors.forename: Francesca
authors.initials: F
authors.lastname: Schiavi
authors.forename: Ricard
authors.initials: R
authors.lastname: Marcos
authors.forename: Nuria
authors.initials: N
authors.lastname: Malats
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Opocher
authors.forename: Ramon
authors.initials: R
authors.lastname: Diaz-Uriarte
authors.forename: Pilar
authors.initials: P
authors.lastname: Santisteban
authors.forename: Alfonso
authors.initials: A
authors.lastname: Valencia
authors.forename: Mercedes
authors.initials: M
authors.lastname: Robledo
mesh_terms: D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D002277:Carcinoma / Q000235:genetics*; D002291:Carcinoma, Papillary; D045744:Cell Line, Tumor; D004843:Epistasis, Genetic; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D000072636:PAX8 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results; D012307:Risk Factors; D000077273:Thyroid Cancer, Papillary; D013964:Thyroid Neoplasms / Q000235:genetics*
chemical_list: D051017:Apoptosis Regulatory Proteins; C106894:FOXE1 protein, human; D051858:Forkhead Transcription Factors; D000072636:PAX8 Transcription Factor; C083325:PAX8 protein, human; D051761:Paired Box Transcription Factors; D012333:RNA, Messenger; D017346:Protein Serine-Threonine Kinases; C115489:STK17B protein, human